rs369246066
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_000719.7(CACNA1C):c.2460+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000448 in 1,552,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000719.7 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENST00000399655.6 | NP_000710.5 | ||
CACNA1C | NM_001167623.2 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 5 | NM_001167623.2 | ENSP00000382512.1 | |||
CACNA1C | ENST00000399655.6 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | NM_000719.7 | ENSP00000382563.1 | |||
CACNA1C | ENST00000682544.1 | c.2550+6G>A | splice_region_variant, intron_variant | Intron 17 of 49 | ENSP00000507184.1 | |||||
CACNA1C | ENST00000406454.8 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 47 | 5 | ENSP00000385896.3 | ||||
CACNA1C | ENST00000399634.6 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 5 | ENSP00000382542.2 | ||||
CACNA1C | ENST00000683824.1 | c.2625+6G>A | splice_region_variant, intron_variant | Intron 18 of 47 | ENSP00000507867.1 | |||||
CACNA1C | ENST00000347598.9 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 48 | 1 | ENSP00000266376.6 | ||||
CACNA1C | ENST00000344100.7 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000341092.3 | ||||
CACNA1C | ENST00000327702.12 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 47 | 1 | ENSP00000329877.7 | ||||
CACNA1C | ENST00000399617.6 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 47 | 5 | ENSP00000382526.1 | ||||
CACNA1C | ENST00000682462.1 | c.2550+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENSP00000507105.1 | |||||
CACNA1C | ENST00000683781.1 | c.2550+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENSP00000507434.1 | |||||
CACNA1C | ENST00000683840.1 | c.2550+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENSP00000507612.1 | |||||
CACNA1C | ENST00000683956.1 | c.2550+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENSP00000506882.1 | |||||
CACNA1C | ENST00000399638.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 47 | 1 | ENSP00000382547.1 | ||||
CACNA1C | ENST00000335762.10 | c.2535+6G>A | splice_region_variant, intron_variant | Intron 18 of 47 | 5 | ENSP00000336982.5 | ||||
CACNA1C | ENST00000399606.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 47 | 1 | ENSP00000382515.1 | ||||
CACNA1C | ENST00000399621.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000382530.1 | ||||
CACNA1C | ENST00000399637.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000382546.1 | ||||
CACNA1C | ENST00000402845.7 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000385724.3 | ||||
CACNA1C | ENST00000399629.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000382537.1 | ||||
CACNA1C | ENST00000682336.1 | c.2535+6G>A | splice_region_variant, intron_variant | Intron 18 of 46 | ENSP00000507898.1 | |||||
CACNA1C | ENST00000399591.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 45 | 1 | ENSP00000382500.1 | ||||
CACNA1C | ENST00000399595.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 45 | 1 | ENSP00000382504.1 | ||||
CACNA1C | ENST00000399649.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 45 | 1 | ENSP00000382557.1 | ||||
CACNA1C | ENST00000399597.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000382506.1 | ||||
CACNA1C | ENST00000399601.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000382510.1 | ||||
CACNA1C | ENST00000399641.6 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000382549.1 | ||||
CACNA1C | ENST00000399644.5 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | 1 | ENSP00000382552.1 | ||||
CACNA1C | ENST00000682835.1 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENSP00000507282.1 | |||||
CACNA1C | ENST00000683482.1 | c.2451+6G>A | splice_region_variant, intron_variant | Intron 17 of 46 | ENSP00000507169.1 | |||||
CACNA1C | ENST00000682686.1 | c.2460+6G>A | splice_region_variant, intron_variant | Intron 17 of 45 | ENSP00000507309.1 | |||||
CACNA1C | ENST00000480911.6 | n.*1067+6G>A | splice_region_variant, intron_variant | Intron 15 of 26 | 5 | ENSP00000437936.2 |
Frequencies
GnomAD3 genomes AF: 0.000289 AC: 44AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000224 AC: 36AN: 160514Hom.: 0 AF XY: 0.000272 AC XY: 23AN XY: 84558
GnomAD4 exome AF: 0.000466 AC: 652AN: 1400548Hom.: 0 Cov.: 31 AF XY: 0.000446 AC XY: 308AN XY: 690678
GnomAD4 genome AF: 0.000289 AC: 44AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 22, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 10, 2023 | The CACNA1C c.2460+6G>A variant (rs369246066) is reported in the literature in a sudden infant death cohort, but without clear disease association (Liebrechts-Akkerman 2020). This variant is also reported in ClinVar (Variation ID: 456955), and is found in the general population with an overall allele frequency of 0.020% (39/191908 alleles) in the Genome Aggregation Database. This is an intronic variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant does not alter splicing. However, since this variant is located within the minimal splice region, the clinical significance of this variant is uncertain at this time. References: Liebrechts-Akkerman G et al. Explaining sudden infant death with cardiac arrhythmias: Complete exon sequencing of nine cardiac arrhythmia genes in Dutch SIDS cases highlights new and known DNA variants. Forensic Sci Int Genet. 2020 May;46:102266. PMID: 32145446. - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with long QT syndrome 8 (MIM #618447), and Timothy syndrome (MIM#601005). Missense variants result in loss of channel inactivation and increased current (OMIM, PMID: 25260352). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (44 heterozygotes, 0 homozygotes). (SP) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely benign, benign and as a VUS (LOVD, ClinVar). It was also observed in a SIDS cohort (PMID: 32145446). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2025 | This sequence change falls in intron 17 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369246066, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 456955). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
CACNA1C-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 05, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at